Type 1 diabetes arises in genetically predisposed individuals as a consequence of the immune-mediated destruction of the pancreatic islet insulin secreting beta cells. The onset of clinical symptoms of diabetes represents a relative endpoint in the chronic progressive decline of beta cell function, and occurs when a preponderance of beta cell mass is lost. The Diabetes Prevention Trial -Type 1 (DPT-1) and Type 1 Diabetes TrialNet have shown: 1) that multi-center cooperative research in type 1 diabetes can be efficiently coordinated on a national and international level and 2) that type 1 diabetes can be predicted with a high degree of accuracy in relatives of patients with type 1 diabetes by the presence of autoantibodies and evidence of pancreatic beta-cell dysfunction. These studies have enabled identification of a large number of patients at the very early stages of their disease prior to the onset of hyperglycemia. Evidence, both in animal models of type-1 diabetes and in human trials, has shown that it is possible to alter the course of beta cell destruction utilizing numerous interventions. Increasingly, novel immunologic agents characterized in investigations of other autoimmune disorders and in the field of organ transplantation have been proposed for the treatment of autoimmune diabetes. One such agent, the anti-CD20 drug rituximab (RituxanR, Genentech, South San Francisco and Biogen) originally developed for treatment of B-cell lymphoma, is now approved for treatment of rheumatoid arthritis, another classically T-cell mediated disease. Results of the TrialNet Rituximab new-onset intervention study, designed by the Co-PI for this study proposal Dr. Mark Pescovitz, has now provided evidence for safety and efficacy of this treatment modality in type 1 diabetes. We propose to extend and expand our participation in Type 1 Diabetes TrialNet as a Clinical Center. As the Clinical Center that proposed the use of rituximab in a new-onset intervention trail and the leader in subject recruitment for that study, IU is uniquely qualified to conduct a prevention study utilizing this agent.